Vol. 294, Issue 3, 975-982, September 2000

Antagonism of ₂-Opioid Receptors by Naltrindole-5'-isothiocyanate Attenuates Heroin Self-Administration but Not Antinociception in Rats¹

Thomas J. Martin, Susy A. Kim, David G. Cannon, Glen M. Sizemore, Di Bian, Frank Porreca and James E. Smith

Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina (T.J.M., S.A.K., D.G.C., G.M.S., J.E.S.); and Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, Arizona (D.B., F.P.)

-Opioid receptors have been implicated in reinforcement processes and antagonists are available that produce long-lasting and selective antagonism of -opioid receptors in vivo. This experiment assessed the contribution of -opioid receptors to the antinociceptive and reinforcing properties of heroin. The effects of the irreversible -antagonist naltrindole-5'-isothiocyanate (5'-NTII) were evaluated on heroin self-administration and hot-plate antinociception in rats. 5'-NTII (10 nmol i.c.v.) shifted the dose-response curve for heroin self-administration downward, increasing the A₅₀ values on the ascending and descending limbs by approximately 0.5 log units and decreasing the maximum by 33%. 5'-NTII (40 nmol i.c.v.) shifted both limbs of the heroin self-administration dose-effect curve 1.2 log units to the right and decreased the maximum by 90%. Heroin self-administration gradually returned to baseline levels over 7 or 17 days after administration of 10 or 40 nmol 5'-NTII, respectively. 5'-NTII (40 nmol i.c.v.) decreased the self-administration of 0.17 mg/infusion cocaine by 40% while having no effect on responding maintained by 0.33 or 0.67 mg/infusion. 5'-NTII attenuated the antinociceptive effects of deltorphin (₂) in a dose-dependent manner while having no effect on antinociception elicited after i.c.v. administration of [D-Pen²,D-Pen⁵]-enkephalin (₁) or [D-Ala²,N-Me-Phe⁴,Gly⁵-ol]-enkephalin (µ). In addition, the antinociceptive effects of heroin were not significantly affected by 5'-NTII (40 nmol i.c.v.). Therefore, 5'-NTII can attenuate the reinforcing effects of heroin at doses that do not affect its antinociceptive effects. Long-acting ₂-opioid antagonists may be beneficial in the treatment of heroin dependence or as adjuncts to reduce the abuse liability of opioid analgesics.